Chronic lipopolysaccharide impairs motivation when delivered to the ventricles, but not when delivered peripherally in male rats

Abstract

Increased neuroinflammation relative to controls is observed in major depression. Moreover, depressive disorders are significantly elevated in conditions which increase neuroinflammation (e.g., brain injury, Parkinson's disease, Alzheimer's disease). To better understand the relationship between neuroinflammation and depression, additional research is needed. The current set of studies made use of the progressive ratio (PR) task in male rats, a stable measure of motivation which can be evaluated daily and thus is ideally suited for examining a potential role for chronic neuroinflammation in depressive-like behavior. Lipopolysaccharide (LPS) was used to induce an inflammatory response. Experiment 1 confirmed prior acute LPS administration experiments for sensitivity of the PR task, with a large effect at 2 mg/kg, a partial effect at 1 mg/kg, and no effect at 0.5 mg/kg. Experiment 2 evaluated a dose-response of continuous s.c. LPS infusion but found no significant elevation in brain cytokines after 14 days at any doses of 0.1, 0.5, 1, or 2 mg/kg/week. Experiment 3 assessed motivation during continuous s.c. infusion of a large 5 mg/kg/week LPS dose and found no significant impairments in motivation, but transient decreases in rates of lever pressing (i.e., only motoric deficits). Experiment 4 measured motivation during continuous ICV infusion of 10.5 μg/kg/week LPS and found significantly decreased motivation without changes to rates of lever pressing (i.e., only motivational deficits). Together these results suggest that the PR task is efficient for evaluating models of chronic inflammation, and that the adaptive response to chronic LPS exposure, even when delivered centrally, may necessitate alternative strategies for generating long-term neuroinflammation.

Keywords: Depression; LPS; Progressive ratio; Rat.

Figure 1.

PR task performance after acute LPS challenge at three different doses. A) Effects on breakpoint for each dose. The 2 mg/kg challenge significantly reduced breakpoint (left panel; p = 0.004), but neither the 1 nor 0.5 mg/kg dose affected it (center, right panels; p’s > 0.105). B) Effects on response rates for each dose. The 2 mg/kg challenge reduced response rates in the early sessions, but not later sessions (left panels; p < 0.001), while the 1 mg/kg challenge led to overall decreased response rates (center panel; p = 0.003), and the 0.5 mg/kg challenge had no effect (right panel; p’s > 0.174).

Figure 2.

Dose-response study (Experiment 2) on frontal cortex cytokine levels after 14 days of peripheral LPS exposure via subcutaneous pump. There were no significant differences in any cytokine level from any dose (p’s > 0.087).

Figure 3.

Dose-response study (Experiment 2) on frontal cortex cytokine levels after 14 days of peripheral LPS exposure via subcutaneous pump. A) Principal components analysis was performed and found that 3 components represented 88.8% of total variance. B) Loadings of PC2 and PC3 indicated a largely pro/anti-inflammatory axis, with CXCL1 as an important, but distinctly orthogonal component. C-E) Group means of the components revealed that the 2.0 mg/kg significantly increased PC2 (p = 0.003).

Figure 4.

PR task performance during exposure to chronic LPS at 5 mg/kg/week. A) LPS had no significant effect on break point (p = 0.255). B) LPS reduced response rates during the early but not later sessions (left vs right panel; p = 0.005). C) Chronic peripheral LPS did not affect number of microglia in the NAC Core or the IL (NAC-C: p = 0.258; IL: p = 0.406). Analysis of the circularity of the cells showed no differences between groups (NAC-C: p = 0.727; IL: p = 0.782). D) Representative images from NAC-C (left) and IL (right).

Figure 5.

PR task performance during exposure to chronic LPS delivered ICV at 10.5 μg/week and histology. A) LPS significant decreased break point (p = 0.043). B) LPS did not affect response rates (p’s > 0.217). C) Chronic ICV LPS significantly changed microglia. In the NAC-C, more circular microglia were increased at the 0.1 circularity index (p = 0.033) and in the IL, the total number of microglia were increased by LPS (p = 0.024), but they were not more circular.D) Representative images from NAC-C (left) and IL (right).